Pituitary tumors, also called pituitary adenomas, develop in the pituitary gland and are usually benign, but in some cases invade surrounding tissues and metastasize (Heaney A. P. and Melmed S. Nature Reviews Cancer 4:285-295, 2004). Symptoms caused by pressure from a larger pituitary tumor may include: visual field defects due to pressure on the optic nerve, increased intracranial pressure, headaches, and problems with the sense of smell. Some pituitary tumors produce increased levels of pituitary hormones, which cause different symptoms. Pituitary tumors are classified into different types according to the hormones they produce or the absence of hormone production.
Corticotroph pituitary adenomas are also called “ACTH-secreting pituitary adenomas”, “Cushing's disease”, or “pituitary-dependent Cushing's syndrome”. Corticotroph pituitary adenomas produce high amounts of adrenocorticotropic hormone (ACTH), which leads to a stimulation of the adrenal cortisol secretion. The increased level of plama cortisol has as effect the inhibition of the ACTH release from normal pituitary cells. Finally, the high levels of ACTH and cortisol in the blood result in high blood pressure, high cholesterol, weight gain or central obesity, thinning of the skin that results in striae, muscle weakness, hyperglycemia, anxiety, insomnia, reduced libido, osteoporosis and depression. Besides humans, Cushing's disease is very frequent in dogs and horses.
Cushing's disease is not to be confused with Cushing's syndrome, which is originated in the adrenal gland or produced by therapeutic treatments with synthetic corticosteroids. In contrast to Cushing's disease, Cushing's syndrome presents normal or low (suppressed) ACTH levels. Thus, pituitary tumors and adrenal tumors represent different clinical entities, being characterized by different symptoms, being differently diagnosed and treated. Some cases of Cushing's syndrome are treated by surgical resection of both adrenal glands to eliminate endogenous glucocorticoids. The resulting lack of cortisol may cause corticotroph tumors in the pituitary gland to grow unchecked. This type of corticotroph adenoma induced by adrenalectomy secretes high amounts of ACTH and MSH and is called Nelson's syndrome.
Prolactin (PRL)-producing pituitary tumors are also called prolactinomas or lactotroph adenomas and their symptoms are galactorrhea and amenorrhea in women, impotence and gynecomastia in men.
Growth hormone (GH)-producing pituitary tumors are also called somatotroph adenomas and produce gigantism or acromegaly, severe headache, heart hypertrophy, hypertension, and diabetes mellitus. Acromegaly results in abnormal enlargement of the hands, feet, ears, nose, lips, and tongue, thickening of the skin and skull, and protrusion of the lower jaw.
Thyroid-stimulating hormone (TSH)-producing tumors secrete TSH and are also called thyrotroph adenomas. The excess of TSH hormone in the blood increases the thyroxin (T4) levels in the blood, resulting in hyperthyroidism and goiter.
Hormone-producing pituitary adenomas are functional tumors that are able to produce or secrete high amounts of hormones such as ACTH, PRL, GH and TSH. The production of such hormones is associated with a variety of side reactions in the body leading to diseases. Hormone-producing pituitary adenomas include corticotroph adenomas, lactotroph adenomas, somatotroph adenomas and thyrotroph adenomas.
In contrast to hormone-secreting pituitary adenomas, non-secreting pituitary adenomas (also called non-functioning pituitary adenomas or null cell adenomas) only produce visual field defects, hypopituitarism, nausea, vertigo, and headaches that are the result of the pressure exerted by the tumor mass on the surrounding tissues.
Pituitary adenomas are usually removed by surgery, but this approach is not always successful. In many cases, only an incomplete resection is achieved and the tumors recur. Radiation therapy is also performed in some cases, but produces side effects and the success of the treatment is low.
Some treatments like the dopamine D2 receptor agonists bromocriptine, cabergoline, or quinagolide are effective only in some cases, mainly in prolactin-secreting pituitary adenomas.
Somatostatin analogs like octreotide and pasireotide (also called Som230) are also partially effective in some cases, mainly in somatotroph and corticotroph pituitary adenomas (Batista D. L. et al., Journal of Clinical Endocrinology and Metabolism 91:4482-4488, 2006; Petersen, S. et al., Journal of Clinical Endocrinology and Metabolism 95:2781-2789, 2010; Feelders, R. A. et al., New England Journal of Medicine 362:1846-1848, 2010; Boscaro M. et al., Journal of Clinical Endocrinology and Metabolism 94:115-122, 2009). However, pasireotide frequently induces severe hyperglycemia and other side effects in patients with Cushing's disease (Kvols L. K. et al, Endocr Relat Cancer 19:657-66, 2012).
Some experimental treatments have been proposed for corticotroph pituitary adenomas such as the PPAR-gamma receptor agonist rosiglitazone (Heaney A. P. et al., Nature Medicine 8:1281-1287, 2002). Rosiglitazone, might increase the risk of cardiovascular disease and bone fractures that are of particular concern in patients with pituitary adenomas, specially corticotroph adenomas that induce osteoporosis. Retinoic acid has been studied in animals, but it has not been tested in human patients due to concerns about its possible side effects (Paez-Pereda M. et al., Journal of Clinical Investigation 108, 1123-1131, 2001). It might cause dyspnea, fever, weight gain, and peripheral edema. Glucocorticoid receptor antagonists such as mifepristone might be used to reduce the symptoms of the high glucocorticoid levels induced by corticotroph tumors (André Ulmann et al.: WO2009/050136). However, GR antagonists do not reduce corticotroph tumor proliferation or ACTH secretion and have side effects such as abdominal pain, uterine cramping, and vaginal bleeding.
In conclusion, up to present there is no effective pharmacological treatment for pituitary adenomas that are secreting or producing hormones. Such a treatment should simultaneously reduce pituitary tumor cell proliferation and hormone secretion without producing serious side effects. As a result, many patients with pituitary tumors, in particular those pituitary tumors that are secreting hormones such as corticotroph adenomas, lactotroph adenomas, somatotroph adenomas and thyrotroph adenomas, remain without an efficacious treatment.
It is the objective of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof, which can be used as pharmaceutically active agents for the treatment of pituitary adenoma, wherein the pituitary adenoma is selected from corticotroph adenoma, lactotroph adenoma, somatotroph adenoma and thyrotroph adenoma, as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.